Scott Linda A, Vass J Keith, Parkinson E Kenneth, Gillespie David A F, Winnie Joseph N, Ozanne Bradford W
Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, United Kingdom.
Mol Cell Biol. 2004 Feb;24(4):1540-59. doi: 10.1128/MCB.24.4.1540-1559.2004.
Invasion is generally perceived to be a late event during the progression of human cancer, but to date there are no consistent reports of alterations specifically associated with malignant conversion. We provide evidence that the v-Fos oncogene induces changes in gene expression that render noninvasive normal human diploid fibroblasts highly invasive, without inducing changes in growth factor requirements or anchorage dependence for proliferation. Furthermore, v-Fos-stimulated invasion is independent of the pRb/p16(INK4a) and p53 tumor suppressor pathways and telomerase. We have performed microarray analysis using Affymetrix GeneChips, and the gene expression profile of v-Fos transformed cells supports its role in the regulation of invasion, independent from proliferation. We also demonstrate that invasion, but not proliferation, is dependent on the activity of the up-regulated epidermal growth factor receptor. Taken together, these results indicate that AP-1-directed invasion could precede deregulated proliferation during tumorigenesis and that sustained activation of AP-1 could be the epigenetic event required for conversion of a benign tumor into a malignant one, thereby explaining why many malignant human tumors present without an obvious premalignant hyperproliferative dysplastic lesion.
侵袭通常被认为是人类癌症进展过程中的晚期事件，但迄今为止，尚无关于与恶性转化特异性相关改变的一致报道。我们提供的证据表明，v-Fos癌基因可诱导基因表达变化，使非侵袭性的正常人二倍体成纤维细胞具有高度侵袭性，而不会诱导生长因子需求或增殖的锚定依赖性发生变化。此外，v-Fos刺激的侵袭独立于pRb/p16(INK4a)和p53肿瘤抑制途径以及端粒酶。我们使用Affymetrix基因芯片进行了微阵列分析，v-Fos转化细胞的基因表达谱支持其在侵袭调节中的作用，独立于增殖。我们还证明，侵袭而非增殖依赖于上调的表皮生长因子受体的活性。综上所述，这些结果表明，在肿瘤发生过程中，AP-1介导的侵袭可能先于增殖失控，并且AP-1的持续激活可能是良性肿瘤转化为恶性肿瘤所需的表观遗传事件，从而解释了为什么许多恶性人类肿瘤在没有明显的癌前过度增殖发育异常病变的情况下出现。
